I like to know that too...
What does it take to be an Arc-520 Volunteer?
As long as the de novo production is only reduced, not stopped, you will observe only an apparent half life, not the real one. In that sense you are right, that the curve under arrowhead inhibition by RNA dicing will go down slower, since new material is still added.
It is also correct to expect somewhat different half lifes at the various phases of surface antigen reduction.
The mechanistic base of the removal is likely to be modified with the amount of activation of the macrophage scavenger system.
Furthermore there might be more than one mechanism of removal, for example spontaneous instability of the particles might contribute and combine with the removal by phagocytosis.
In physics the deeper reasons and mechanisms of particle decay are constant and it therefore follows a perfect exponential function.
i know half life in physics terms. but may you put light in hbsag context. is it the time to reduce hbsag from some initial value to its half value?
if so there can be two possibilities:
first possibility, if stimulated immune system is the cause of hbsag reduction (as in above acute case with no new hbsag production phase).....that means it is immune dependent and non linear with the initial hbsag value as immune system slows down complicatedly as hbsag becomes small and ofcourse this rate of clearance may be different for different people.
another possibility is that if this reduction is due to some drug that directly act on hbsag (as replicor) , then reduction rate should be drug dose dependent.
so can we expect exact matching between the life times calculated from above two datas which targets hbsag differently.
if they shouldn't be the same then from your calculations it seems that repliicor+ nucs combination would be much better than arc520 alone. as replicor is faster in clearing hbsag concentrations.
please correct and clearify.
Thank you for that quick analysis. It is not everyday that you see scientists at work.
I agree the half life of 8 days seems too long. This question was never accessible experimentally in patients, since elimination and production are equal at equilibrium.
So for a moment I believed the bloggers report of estimations from acute HBV, where they assumed there was a phase, where de novo production was close to zero and the downwards curve therefore allowed the calculation of the half life of surface antigen particles circulating.
But strangely, we have right now by happenstance a very simple and useful source for the determination of this half life. In the replicor trials, the release of the surface antigen is completely blocked and the resulting downwards curve therefore shows the upper limit for its elimination kinetics and the half life is directly visible from the poster information. It takes four to six weeks to come down from rather high starting values to the detection limit. Ten half lifes reflects about a reduction by a factor of one thousand. Thus we can see that the half life is in the range of three to four days.
This is the same concept that was used to determine virion half lifes once replication blocking antivirals became available.
it should not be taken otherwise. ok dear, nobody here is denying anybodies faith,sometimes it gives strength to fight. but here we are gathered to discuss and care about policies,aspects and treatment options of hep b not the existance or working phiosophy of lord/god. we are with you to disscuss any thing scientific or managerial which is related to hep b future and helpful to you in physical terms/tretment.
we accept psychological/social aspects of hep b are least disscussed here, if you want to discuss them please feel free to discuss as a new thread as they are indifferent part of hep b. still politely very politely please dont argue about gods. offcourse god may put his kindness to all of us and to those who are working for us and our healthy future.
your statement is totally refused .. Allah is the creator of every things .. to examine our patience ..
sorry but the lord has nothing to do with our community, this is scientific discussion and patient to patient discussion, religion is off topic and does not belong here nor we want to discuss it here
dont speak like that. your comments are discouraging. trust in the Lord dear.
promising treatment. They need a subcutaneous form though. sounds like repeated application may be necessary.
I do remember the discussion well. Yes, functional cure is a term coined by the American scientists. It has been used to describe the current treatments for HIV/AIDS. I read somewhere that Dr Gish once remarked that for most HBV patients, he can now just prescribe them a daily pill.
I must say, I am a bit surprised by the fairly long(?) half-life of serum HBsAg.
Considering this phase I trial in healthy volunteers, the question arises what they can discover in this setting, aside from the absence of detectable toxic short term side effects. They cannot determine if the delivery system to the hepatocytes work, since there is no indicator of such delivery available. I doubt that there are liver biopsies planned to detect the compound after application inside the liver cells.It will be interesting to see alt responses after dosing, that hopefully are absent, considering the bee venom peptide that is used to burst endocytosed drug carrier containing microsomes for final delivery into the cytosol.
Only once they use HBV patients they will be able to assess delivery and inhibition effectiveness, the first being deductible from the second.
In general, we have discussed the outlook, promises and problems with the arrowhead approach in previous posts.
It is useful to ask the question what the expression "functional cure" realistically means.
In a fairly recent post by Stefano, a Taiwan study was presented, that showed that at the lower limit of detection of the quant surface antigen assay, that is 0.05 IU, there are still 42 million surface antigen particles per ml of plasma present.
At one iu that would mean about one billion per ml.
If a patient with 4000 IU, like Stefano, had a 90% reduction by the arrowhead treatment, then it would be 400 billion of these particles per ml after the treatment.
I would like to point out, that the immunosuppressive effect of the hbsag, in its nonspecific variety, is likely caused by a sheer clogging of macrophages and dendritic cells processing machinery by this huge amount of trash antigen. No wonder that the half life is eight days, and even more with higher antigen loads.
The specific effect of the huge hbsag burden is sending hbsag specific cd8 tcells cells into tolerance and apoptosis all over the body wide presentation.system.
Thus, not only will repeat dosing be necessary, it also remains to be seen if the reduction achieved has a chance to re activate the effective parts of the immune response, like it was quite convincingly seen with the replicor treatment, which achieved a 99.99% reduction of circulating surface antigen.
The arrowhead approach, if there are no relevant side effects from long term therapy, might well achieve a reduction in immune attack on the liver, if the virion production is also substantially reduced. Virion numbers are the strongest inducers of immune attacks onto the liver cells. Thus the hepatitis and fibrosis progression might be reduced. Thus they hold the potential to replace the never ending antiviral treatment with a permanent interfering RNA treatment, if less side effects can be anticipated and it can be priced for long term treatment.
I assume that is what arrowhead means by a functional cure.
I think it is really unrealistic to expect a single dose of ARC520 to produce a functional cure. The blogger seems to raise the expectation himself, but is now discovering that a simple knock down of antigens does not lead to immediate re-awaking of immune response against the chronic HBV infection.
It is interesting to see what he discovers next.
may be they are working on how to make therapy only partially effective on hbsag clearance, because thats the fact for being in money making bussiness.
New Therapeutic Approaches to Cure Chronic Hepatitis B Virus Infection
Read more: New Therapeutic Approaches to Cure Chronic Hepatitis B Virus Infection | Medindia http://www.medindia.net/news/new-therapeutic-approaches-to-cure-chronic-hepatitis-b-virus-infection-118135-1.htm#ixzz2aSGog1vF
one thing must be told strongly to these ARC-520 and other fame wanted people that they must come with really new, good, reliable, sustained, cost effective therapy.....otherwise no need to just make news for their company fame and shares.
whatever you pharma wants to do..do fast..even go for non traditional-non FDA way....as now there is compitition. use yours hooks and crooks.....good luck pharmas..
the good thing with delay in cure therapy is that we are now more informative and not going to accept any thing less than nearly a cure or complete cure..
I mean just look at this how they do trials.. "Each dose cohort includes 6 subjects randomized at ratio of 1:2"
Only 6 people. That is nothing. Why not Take 100-200 people? And see what the result would be.
anyway, I hope ARC-520 works, but 2020 that is a long 7 years ahead..
Repeated interferon treatments of HBV patients produce results, In the 80s they did that with good success.
So has there really been any real progress since then in terms of HBV treatment? NO..
It only went backwards, they have fazed out interferon use, and replaced it with anti hiv drugs that were originally developed to treat cancer.
So there you have it..
I say if more treating centers would use Alinia plus Interferon with high dozes of Vitamin D3 and C.. with UBI with ozone therapy and or Plasmapheresis - we would have very good results in hbv treatment in 6-12 months.
But all this is being disregarded, till they come up with a quick fix solution for hbv. And that will most likely be gene therapy.
But again, based on what is shown Repicor has the cure already. Why not use it?
The more I am sick with HBV the more I learn about it, the more I realize that the problem is made bigger then it really is, regarding treating it..
Speaking of unfounded statements....
But How about trading surface antigen quant for 700ml of plasma every time? This is the company Scantibodies in San Diego that you recommended. That plasma they collect is worth a lot btw. So there is just one example of taking advantage of people. People that are sick.
So lets not shy away from real problems how corrupt the medical system is... Why it is like that? because it is a business. Which it cannot be.. So it is a social problem really.
If they were honest they would treat people with interferon first. They would do immune therapies, remove oxidative stress to free the body from toxins, optimize the vitamin intake levels, so the body can fight HBV better.
Instead they give us drugs that slow down cell growth (nucs) thus virus lives longer and has no need to make copies to survive,that is why VL goes down eventually while on these drugs. But adding more toxins in the process to the body. And fatty liver development as a side of nucs is just one example. That is why it is written as a side effect of nucleoside analogs
So it is a wrong treatment strategy.
And with technology available today dont you think they know it? proof of it in what happens when medicine is stopped. VL goes through the roof in most cases when nucs are stopped.
So why giving it in the first place? For HIV it makes sense, because the virus enters every cell of humant body and damages it. So you have to slow it down, just like they wanted cancer that these drugs were originally developed for.
Hep B treatment is not a problem even now with available drugs. Problem is to find a doctor who is honest and that will do what is best for the patient. Finding a doctor that will not first call health insurance to see what they say, but the one that will do what is right.
Do they other there in UCSD in their brand new antiviral center use Alinia with Interferon? Alinia plus Zadaxin? Which is more affective then what is available today. No, it is only nucs. Why is that? Same thing in UCLA is happening. TDF or ETV and forget about it! You call this options?
Or why doing clinical trials on only what that the drug company has paid for? So there you go an example of a steered research in one direction.
Public funds must be available for this. Then there would be HBV cure already. Because what we have now an indefinite maintenance therapy is really what is driving the cost of health care.
Only now in these past couple of years big pharma is starting to move towards immune enhancer therapies. Towards gene therapy, because people all over HBV web are waking up to how worthless these drugs are that we take.
Why won't these Drug companies ever come to these forums, and talk to us, how can things be done better?
You don't see anybody here from Replicor or Gilead. Why is that? In every industry if we call it that, the manufacturers engage their audience for feedback. Here is just dead silence. With promises for better tomorrow of 2020.
HCV is now considered curable. HCV is easier to cure because there is no stable ccdna hiding in the cell nucleus like hepatitis B.
Cure for HBV?
Well Replicor has it? What is stopping them from using it?
It is an economic issue. Insurance companies don't want to pay for treatments, and frankly they only care about cost
Drug companies are not interested in eradicating the disease not to loose the market. We are a market!
HCV btw is a much harder virus then HBV. But because that community is more active they have better treatments.
The chimpanzee HBV data on ARC520 showed that while HBV viral DNA and the HBeAg were greatly reduced almost immediately following onset of gene silencing, HBsAg elimination lagged behind: a 50% reduction following ~8 days and another 50% reduction following 15-20 days. This raised questions in the minds of some readers here about the potency of ARC520 in real patients.
My response was that this most likely reflects a slow HBsAg elimination even in the absence of new HBsAg production. This was also speculated on in the ARC520 analyst day webcast by Arrowhead Research.
Thanks to the patent application by GSK which I discussed here last night, I was finally able to find a good reference on HBV elimination in real patients (not mice and woodchucks). In this paper by Chulanov et al., the kinetics of viral components were followed in patients with acute hepatitis caused by HBV. In this setting, it is assumed that almost no new viral production occurs thus facilitating the determination of half-lives.
Strikingly, the observations were entirely consistent with the chimpanzee data: whereas the HBV DNA and HBeAg half-lives were on the order of 1-2 days, the half-life of HBsAg was ~8 days. What is more, in patients with high viral titers (remember, the chimpanzee had exceptionally high titers) to start with, the half-life increased. This means that even if there was almost complete knockdown of HBsAg with ARC520 in the chimpanzee, HBsAg after 8 days would still be predicted to be ~50% of the starting value…exactly what was observed. The fact that a 75% reduction (i.e. another halving) was observed after 15-20 days suggest that RNAi gene silencing was still near its peak even 2 weeks following ARC520 administration. Thus, the chimpanzee data are entirely consistent with a high potency of ARC520 ‘in the real world’.
The slow HBsAg kinetics, however, have important implications for the dosing regimen and expectations for the outcome of the single-dose phase IIa Hong Kong study. Whereas I had speculated that functional cures may be seen in the results from this study around a year from now, I now have to moderate my expectations. This is because a 8 day half-life predicts that a 90% reduction of HBsAg, which seems to be a benchmark set by the companies, could theoretically be achieved only 3-4 weeks after drug administration. At this point, however, the RNAi activity is expected to wane such that at least 2 or 3 doses every 10 to 14 days would be needed to safely achieve the 90%+ knockdowns in most patients.
As a result, it may be worth for the company to seek an extension for the Hong Kong study. This, however, would likely require a degree flexibility by the Hong Kong authorities since the 9-month chronic tox studies are only beginning. If seeking such an extension would mean delays in the clinical development timelines, I would do just the single-dose as the multi-dose study should begin in the second half of 2014 anyway.
Update: According to information provided by Arrowhead Research yesterday, following just 2 weeks of study initiation, dosing with ARC520 has already been completed for 2 out of the 6 ascending dose cohorts. Accordingly, the company remains on track to report data in Q4 or even by the end of Q3 and initiate the Hong Kong study soon thereafter.